Magnesium omeprazole

ABSTRACT

Improved process to produce magnesium omeprazole substantially amorphous with pharmaceutically acceptable low level of methanol and solid pharmaceutical compositions.

This application is the US national phase of international applicationPCT/CA00/00901 filed Aug. 4, 2000 which designated the U.S.

FIELD OF THE INVENTION

The present invention relates to an improved form of magnesiumomeprazole, a process for making same, and pharmaceutical compositionssame.

BACKGROUND OF THE INVENTION

The compound known under the generic name omeprazole is described inEuropean patent 0005129.

Omeprazole is useful for inhibiting gastric acid secretion and hasgastric mucosa protective activity in mammals and man. Omeprazole may beused for prevention and treatment of gastric acid related disorders andgastrointestinal inflammatory diseases in mammals and man, including forexample gastritis, gastric ulcer and duodenal ulcer.

The term “omeprazole” as used in this specification designates theneutral form of the compound, that is the form without a salt-formingcation present.

Certain salts of omeprazole are described in European patent 0124495.

In EP 0124495, example 5 specifically discloses the synthesis ofmagnesium omeprazole dihydrate, and example 6 specifically discloses thesynthesis of magnesium omeprazole anhydrate. Manufacturing of thedescribed magnesium omeprazole salts presents significant difficulties.

The process of manufacture and isolation of the dihydrate according toexample 5 is relatively complex. It requires making the sodium salt,adding a solution of magnesium chloride to obtain a precipitate,removing water by centrifuging the precipitate, washing the precipitatewith deionized water until no Cl⁻is detectable, drying in air, grinding,and the drying in vacuum at 40° C. for 24 h. Moreover, because theresulting magnesium omeprazole dihydrate is crystalline, the rate ofdissolution in intestinal fluid is relatively slow, unless the materialis milled to a relatively fine particle size.

The process of making the anhydrate according to example 6 is simpler.Magnesium is reacted with methanol to give a solution of magnesiummethoxide in methanol. The solution is added to a solution of omeprazolein methanol, the quantity of omeprazole being one mole for each twomoles of magnesium. The methanol is then evaporated to give acrystalline solid, which is magnesium omeprazole anhydrate. However, theanhydrate as made by this process is also not without a problem. As themagnesium omeprazole precipitates from the solution upon evaporation ofthe methanol, residual methanol is entrapped in the solid particles andcannot easily be removed by evaporation. Methanol is toxic and highlevels are generally considered unacceptable in pharmaceuticalchemicals.

Canadian patent 2166794 describes what is said to be an improved form ofmagnesium omeprazole dihydrate, which has a higher degree ofcrystallinity than that of example 5 of EP 0124495. This form has amethanol content of less than 0.1%. However, like the product of example6 of EP 0124495, it is a crystalline dihydrate, and the process ofmanufacture is relatively complex. According to Canadian patent 2166794,the degree of crystallinity of a sample made according to example 6 ofEP 0124495 was 67%, whereas the degree of crystallinity of the improvedform is at least 70%.

Canadian patent application No. 2254572 discloses improved processes forthe production of magnesium omeprazole crystalline dihydrate. Thedisclosure reviews the prior art, and in particular, in relation to theanhydrate of example 6 of EP 0124495, states as follows: “This procedurecannot be practised on a large scale because of the need to evaporate todryness. It has been found that unacceptable and potentially dangerousamounts of methanol become trapped in this solid, making itpharmaceutically unacceptable.” The processes of Canadian patent 2254572are again relatively complex.

Improved processes for the production of magnesium omeprazolecrystalline dihydrate are also described in PCT Publication No. WO97/4114. The degree of crystallinity of the product of example 1 is saidto be 80%. Again, the processes disclosed are relatively complex.

In summary, the only magnesium omeprazole according to the prior artthat has an acceptably low level of methanol is magnesium omeprazolecrystalline dihydrate, which has a degree of crystallinity of 67% orhigher and is produced only by relatively complex processes.

In light of the foregoing, the object of the present invention is toproduce magnesium omeprazole that has acceptably low levels of methanol,but is substantially amorphous (non-crystalline), and can be produced bya simple process.

BRIEF SUMMARY OF THE INVENTION

Magnesium omeprazole of the present invention is made by reactingmagnesium in a lower alcohol to form magnesium alkoxide, addingomeprazole in a quantity of about two moles per mole of magnesium, andflash-evaporating the alcohol, so as to form a solid precipitate withoutallowing the growth of crystals or particles that entrap the alcohol atunacceptable levels. The resulting material is substantially amorphous(non-crystalline).

DETAILED DESCRIPTION OF THE INVENTION

In the process of manufacture of magnesium omeprazole according to thepresent invention, magnesium is reacted in a lower alcohol, preferablymethanol, to form a solution of magnesium alkoxide in the alcohol.

The atomic weight of magnesium is 24.3 and the molecular weight ofomeprazole is 345.4. Since magnesium is divalent, the amount ofmagnesium required to convert 345.4 grams of omeprazole to magnesiumomeprazole is 12.15 grams.

Hence 35.2 grams of magnesium is needed to convert 1 kilo of omeprazoleto magnesium omeprazole.

The process of converting 1 kilo of omeprazole to magnesium omeprazolethus begin with reacting 35.2 grams of magnesium in a lower alcohol,preferably methanol. The minimum amount of methanol needed to fullyreact and dissolve 35.2 grams of magnesium is about 1000 grams.

When the magnesium is immersed in the alcohol, the reaction will beevident from the generation of hydrogen bubbles, and the reaction willbe complete when all the magnesium has been consumed and theeffervescence has ceased. All of the magnesium will then be present asmagnesium alkoxide in the alcohol (i.e. magnesium methoxide in methanol,if methanol is used as the alcohol).

The omeprazole can then added directly to the magnesium alkoxidesolution. Attentively, the omeprazole may first be dissolved in analcohol or another organic solvent that is miscible with the alcoholused to make the magnesium alkoxide, and the resultant solution may thenbe added to the magnesium alkoxide solution.

Where methanol is used as the sole solvent, a total of only about 1.5kilos is needed for converting 1 kilo of omeprazole to magnesiumomeprazole in solution by the methanol.

Hence, using quantities based on 1 kilo of omeprazole, the simplest andbest procedure is to react 35.2 grams of magnesium in about 1.5 kilos ofmethanol, wait until the magnesium has been fully reacted, and then addthe 1 kilo of omeprazole to the solution and stir to dissolve. Theresulting solution will be a solution of magnesium omeprazole equivalentto 1 kilo of omeprazole in methanol.

In order to obtain solid magnesium omeprazole that is substantially freeof organic solvent (i.e. substantially free of methanol, if methanol isused), it is then necessary to eliminate the solvent.

It has been found that this can be done by “flash-evaporating” thesolvent. Flash-evaporating will be understood to mean evaporating insuch a way as to avoid the precipitation of crystals or large particleswhich entrap the alcohol.

One method of flash-evaporating the solvent is to mix the solution intoa solid excipient such as, for example, microcrystalline cellulose sothat a damp mass is formed. The mass can then be dried in a conventionaloven, a fluid bed drier, or under vacuum to remove the solvent. Becausethe solution has been dispersed throughout the solid excipient, as thesolvent evaporates, the omeprazole magnesium is deposited as a thinlayer over the surface of the particles of the solid excipient and doesnot precipitate as crystals or large granules, so that there is littleor no entrapment of solvent.

The preferred way of flash-evaporating the solvent is by spray-dryingthe solution.

It has been found that, by such process, magnesium omeprazole can bemade having a residual solvent content substantially lower than can beachieved by simply evaporating the solvent from the solution undervacuum.

The residual organic solvent content by weight of the magnesiumomeprazole made according to the present invention will be under 7%,preferably under 5%, more preferably under 2%, and most preferably under1%.

The degree of crystallinity of the obtained product can be measured withpowder X-ray diffraction (XRD) as described in WO97/4114 as follows: Athin layer of the triturated sample is smeared onto a cut silicon singlecrystal zero background holder which is rotated during the measurement.Cu Kα radiation and constant or automatic antiscatter and divergenceslits are used to obtain a diffractogram with 2θ from 1 or 2° to atleast 35°.

The degree of crystallinity is calculated with the formula

degree of crystallinity=100+C/(A+C)

C=the area from the peaks in the diffractogram (“the crystalline area”),

A=the area between the peaks and the background (“the amorphous area”).

Area calculations are performed for 2θ between 4-33°. The lowestintensity value found in this interval is chosen as the constantbackground and subtracted from the area A. When constant slits are used,the increased background at low angles due to the influence from theprimary beam is also subtracted from the area A.

The degree of crystallinity of magnesium omeprazole according to thepresent invention is under 67%, as compared to 67% or higher formagnesium omeprazole crystalline dihydrate according to the prior art.

The degree of crystallinity will preferably be under 60%, morepreferably under 50%, and most preferably under 25%.

If the magnesium omeprazole of the present invention is made in anenvironment and using excipients (including the air or other gas usedfor drying in the spray-dry process) that is completely free of water,the magnesium omeprazole will be anhydrous. However, pure anhydrousmagnesium omeprazole is hygroscopic and it will readily absorb waterfrom air until it reaches an equilibrium water content of about 5% to8%, depending on the relative humidity of the air. This is notproblematic, as it does not adversely affect stability.

The magnesium omeprazole of the present invention will be furtherprocessed into pharmaceutical compositions such as, for example, tabletsfor oral administration. The tablets will preferably be enteric coatedto protect the magnesium omeprazole from the effects of gastric acid.

The invention will be further understood from the following examples,which are intended to be illustrative and not limiting of the invention.

EXAMPLE 1

1.76 g of pure magnesium was added to 800 g of methanol in a 1000 mLglass flask. The flask was closed with a loose-fitting stopper (loose toallow hydrogen gas to escape), and the flask was allowed to sitovernight.

The next morning it was observed that the magnesium had all beenconsumed and that the effervescence had ceased, resulting in a slightlyhazy solution of magnesium methoxide in methanol. 50 grams of omeprazolewas then added to the contents of the flask and the contents werestirred for several minutes until the omeprazole dissolved to form asolution of magnesium omeprazole in methanol.

EXAMPLE 2

To produce a reference sample of magnesium omeprazole anhydrateaccording to the prior art (i.e. example 6 of EP 0124495), about 20% ofthe solution from step 2 was transferred to a 1000 mL beaker. The beakerwas then placed in a vacuum oven for drying under vacuum at 50° C. for aperiod of 4 hours. At the end of this time, a solid material remainedthat had no evident odour of residual methanol. This solid material wastested to determine the level of residual methanol, which was found tobe 7.2% by weight.

EXAMPLE 3

To produce magnesium omeprazole of the present invention, the balance ofthe solution of Example 1 was spray-dried on a Yamato® spray-dryer,using an inlet air temperature of about 140° C. and outlet airtemperature of about 70° C.

The resulting dry material was a fine powder, which appearednon-crystalline and also had no evident odour of residual methanol. Thepowder was tested to determine the level of residual methanol, which wasfound to be 0.7%.

This powder was examined for crystallinity by powder X-ray diffraction,and it was found that the powder was substantially amorphous(non-crystalline), having a degree of crystallinity of under 25%.

EXAMPLE 4

The following ingredients were mixed together in the proportions shown:

Magnesium omeprazole 21.  Anhydrous lactose 131.   Croscarmellose sodium6.4 Magnesium stearate 1.6 160.  

The mixture was compressed into tablets having a weight of 160 mg pertablet, so that each tablet contained 21 mg of magnesium omeprazole,which is equivalent to about 20 mg of omeprazole.

A sub-coating comprising hydroxypropyl methylcellulose dissolved inwater was then applied to the tablets by spray-application in aside-vented coating pan.

An enteric coating was then applied over the sub-coating byspray-application of methacrylic acid copolymer aqueous dispersion, withtriethyl citrate dissolved therein as plasticizer.

What is claimed is:
 1. A process of producing magnesium omeprazole, saidprocess comprising the steps of: (i) reacting magnesium with a loweralcohol to produce magnesium alkoxide in solution in the lower alcoholas solvent, (ii) adding omeprazole to the solution, the amount ofomeprazole being about 2 moles per mole of magnesium, and (iii)flash-evaporating the solvent yielding magnesium omeprazole having adegree of crystallinity of under 67% by weight and having a residualorganic solvent content of less than 7% by weight.
 2. A process of claim1 wherein the lower alcohol is methanol.
 3. A process of claim 1 whereinthe flash-evaporation is done by spray-drying the solution.
 4. Magnesiumomeprazole having a degree of crystallinity of under 67% by weight andhaving a residual organic solvent content of less than 7% by weight. 5.Magnesium omeprazole of claim 4 having a residual organic solventcontent of less than 5% by weight.
 6. Magnesium omeprazole of claim 4having a residual organic solvent content of less than 2% by weight. 7.Magnesium omeprazole of claim 4 having a residual organic solventcontent of less than 1% by weight.
 8. Magnesium omeprazole of claim 4having a degree of crystallinity of under 60%.
 9. Magnesium omeprazoleof claim 4 having a degree of crystallinity of under 50%.
 10. Magnesiumomeprazole of claim 4 having a degree of crystallinity of under 25%. 11.A solid pharmaceutical composition for oral administration comprisingmagnesium omeprazole of claim
 4. 12. A composition of claim 11 in theform of that tablet.
 13. A composition of claim 12 wherein the tablet isenteric coated.